What is the recommended work‑up and first‑line antiviral therapy for a treatment‑naïve adult with chronic hepatitis C, considering genotype, liver fibrosis, cirrhosis, renal function, HIV co‑infection, pregnancy, and other comorbidities?

Hepatitis C Management

First-Line Treatment Recommendations

All treatment-naïve adults with chronic hepatitis C should receive a pangenotypic direct-acting antiviral (DAA) regimen: either sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks or glecaprevir/pibrentasvir for 8–12 weeks (duration based on cirrhosis status). 1, 2, 3

Preferred Pangenotypic Regimens

• Sofosbuvir/velpatasvir is the preferred first-line option, administered as a single tablet (400mg/100mg) once daily for 12 weeks, achieving 98% sustained virologic response (SVR) rates across all genotypes (1–6) regardless of treatment history or cirrhosis status. 2, 3

• Glecaprevir/pibrentasvir serves as an equally effective alternative with treatment duration stratified by cirrhosis: 8 weeks for patients without cirrhosis and 12 weeks for those with compensated cirrhosis (Child-Pugh A). 1, 2, 4

Pre-Treatment Work-Up

Mandatory Testing Before Initiating DAAs

• HCV RNA quantitative testing to confirm active viremia (using assays with lower limit of quantification ≤25 IU/mL). 1, 3, 4

• HCV genotype and subtype determination, particularly distinguishing genotype 1a from 1b, as this affects certain regimen selections and resistance-associated substitution (RAS) considerations. 1, 2, 3

• Fibrosis staging using non-invasive methods:

  • Calculate FIB-4 score as the primary screening tool. 1, 5
  • If FIB-4 >3.25, presume cirrhosis is present. 1
  • Alternative non-invasive methods include transient elastography (FibroScan stiffness >12.5 kPa indicates cirrhosis), proprietary serologic tests (FibroSure, Enhanced Liver Fibrosis Test), or clinical evidence (liver nodularity/splenomegaly on imaging, platelet count <150,000/mm³). 1, 5, 6, 7

• Comprehensive medication reconciliation including over-the-counter drugs and herbal/dietary supplements, with drug-drug interaction assessment using AASLD/IDSA guidance or University of Liverpool drug interaction checker. 1, 2

• Baseline liver function tests and complete blood count. 1

• HIV and HBsAg testing to identify coinfection. 1, 2

• Pregnancy testing in women of childbearing potential. 1

• Renal function assessment (eGFR calculation) to guide regimen selection. 1, 2

Treatment Algorithm by Clinical Scenario

Treatment-Naïve Without Cirrhosis (Simplified Treatment Eligible)

Recommended regimens:

• Glecaprevir/pibrentasvir (300mg/120mg) taken with food for 8 weeks. 1, 4
• Sofosbuvir/velpatasvir (400mg/100mg) for 12 weeks. 1, 2

SVR rates: >95% across all genotypes. 2, 4

Treatment-Naïve With Compensated Cirrhosis (Child-Pugh A)

Recommended regimens:

• Glecaprevir/pibrentasvir for 12 weeks (extended from 8 weeks due to cirrhosis). 1, 2, 4
• Sofosbuvir/velpatasvir for 12 weeks. 2

SVR rates: 98–99% across all genotypes. 2, 4

Genotype-Specific Considerations for Alternative Regimens

Genotype 1a:

• Ledipasvir/sofosbuvir 90mg/400mg daily for 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis). 1, 2
• Treatment-experienced patients with cirrhosis should add weight-based ribavirin (1000mg if <75kg, 1200mg if ≥75kg) for 12 weeks. 1

Genotype 1b:

• Ledipasvir/sofosbuvir for 12 weeks without ribavirin regardless of cirrhosis status. 1, 2

Genotype 3 (higher complexity):

• Without cirrhosis: glecaprevir/pibrentasvir for 8 weeks or sofosbuvir/velpatasvir for 12 weeks. 2, 4
• With compensated cirrhosis: glecaprevir/pibrentasvir for 12 weeks or sofosbuvir/velpatasvir + ribavirin for 12 weeks. 2
• Alternative for compensated cirrhosis: sofosbuvir/velpatasvir/voxilaprevir for 8 weeks (96% SVR). 2

Genotypes 2,4,5,6:

• Pangenotypic regimens (sofosbuvir/velpatasvir or glecaprevir/pibrentasvir) are preferred with durations as above. 2, 4

Special Populations

Severe Renal Impairment (eGFR <30 mL/min/1.73 m²)

This population is NOT eligible for simplified treatment. 1

Preferred regimen:

• Glecaprevir/pibrentasvir is the regimen of choice, achieving 97–98% SVR in CKD stage 4–5 including dialysis patients (EXPEDITION-5 trial). 2, 4

Alternative:

• Elbasvir/grazoprevir achieving 94–98% SVR (C-SURFER trial). 2

Critical contraindication:

• Avoid all sofosbuvir-based regimens when eGFR <30 mL/min/1.73 m² due to renal excretion concerns and lack of FDA approval at this level of renal function. 1, 2

Mild-to-moderate renal impairment (eGFR 30–80 mL/min):

• No dosage adjustment required for any approved DAA regimen. 1

HIV/HCV Coinfection

This population is NOT eligible for simplified treatment. 1

Treatment approach:

• Use the same HCV treatment regimens as HCV monoinfected patients with identical virologic outcomes. 2, 3

Critical drug-drug interactions to avoid: 2

• Sofosbuvir/ledipasvir with tenofovir disoproxil fumarate plus ritonavir-boosted protease inhibitors (potentiates tenofovir nephrotoxicity). 1
• Paritaprevir/ombitasvir/dasabuvir with efavirenz, etravirine, nevirapine, or elvitegravir/cobicistat. 2

Mandatory step:

• Verify antiretroviral drug interactions before prescribing using specialized interaction checkers. 2, 3

Pregnancy

No DAA regimen is FDA-approved for use during pregnancy. 2

Recommendation:

• Defer therapy until after delivery unless severe extrahepatic disease mandates immediate treatment. 2

Decompensated Cirrhosis (Child-Pugh B or C)

This population is NOT eligible for simplified treatment. 1

Recommended regimens:

• Sofosbuvir/ledipasvir + ribavirin for 12 weeks. 2
• Sofosbuvir/velpatasvir + ribavirin for 12 weeks. 2
• Sofosbuvir/daclatasvir + ribavirin for 12 weeks. 2

Ribavirin dosing:

• Start at 600mg daily and adjust based on tolerance (not weight-based in decompensated cirrhosis). 1, 2

Critical contraindication:

• Avoid glecaprevir/pibrentasvir in decompensated cirrhosis (Child-Pugh B or C) as it is contraindicated. 4

Liver Transplant Recipients

This population is NOT eligible for simplified treatment. 1

Recommended regimen:

• Sofosbuvir/velpatasvir + ribavirin for 12 weeks applies to both pre- and post-transplant settings. 2

Prior Treatment Experience

Treatment-experienced patients (prior pegIFN/RBV or sofosbuvir) without prior NS5A inhibitor or protease inhibitor exposure:

• Use the same pangenotypic regimens as treatment-naïve patients. 2

Prior NS5A inhibitor failure:

• Sofosbuvir + protease inhibitor (grazoprevir/elbasvir or simeprevir) + ribavirin for 12 weeks (genotype 1b or 4 without cirrhosis) or 24 weeks (genotype 1a or with cirrhosis). 2

Critical Drug-Drug Interactions

Absolute Contraindications (Significantly Decrease DAA Concentrations)

• P-glycoprotein (P-gp) inducers: rifampin, St. John's wort. 2, 3
• Moderate-to-strong CYP3A4 inducers: carbamazepine, phenytoin, phenobarbital, rifampin, efavirenz. 2, 3

Important Monitoring for Specific Medications

• Diabetes medications: Inform patients of potential for symptomatic hypoglycemia; monitor glucose closely. 1
• Warfarin: Monitor INR for subtherapeutic anticoagulation. 1

On-Treatment and Post-Treatment Monitoring

During Treatment

• No routine laboratory monitoring required for most patients. 1
• Optional in-person or telehealth visit for patient support, symptom assessment, and new medication review. 1
• For patients with cirrhosis or decompensated disease, monitor liver function tests and for signs of decompensation. 2

Post-Treatment

• HCV RNA at 12 weeks post-treatment (SVR12) is the primary measure of cure, achieved in >99% of patients who reach this endpoint, representing viral eradication. 2, 3
• SVR12 is defined as HCV RNA <15 IU/mL (below lower limit of quantification) at 12 weeks after treatment completion. 4

Treatment Prioritization

Immediate Treatment Priority (Do Not Defer)

• Advanced fibrosis (≥F3) or any cirrhosis. 2
• Pre- and post-liver transplant patients. 2
• Severe extrahepatic manifestations (symptomatic cryoglobulinemia, HCV immune complex nephropathy). 2
• Hepatocellular carcinoma. 2
• Individuals at high risk of HCV transmission. 2

Can Schedule Treatment (More Flexible Timing)

• Minimal or no fibrosis (F0–F2) without other high-risk features, though treatment should still be scheduled rather than indefinitely deferred. 2

Expected Outcomes and Clinical Benefits

Virologic Outcomes

• SVR rates >95% in most patient populations with modern pangenotypic DAA regimens. 2, 3, 4
• SVR rates 97–99% in treatment-naïve patients without cirrhosis. 2, 4
• SVR rates 92–98% in patients with compensated cirrhosis. 2, 4

Long-Term Clinical Benefits of Achieving SVR

• 70–90% reduction in liver-related mortality. 2
• 70–90% reduction in overall mortality. 2
• 75–90% reduction in hepatocellular carcinoma incidence. 2
• Prevention of hepatic decompensation. 2
• Improvement in liver histology and fibrosis regression. 2, 3
• Resolution of extrahepatic manifestations. 2, 3
• Reversal of cerebral MRI abnormalities linked to neurocognitive impairment. 2

Important Caveats

• Patients with advanced cirrhosis retain residual HCC risk despite SVR and require ongoing surveillance. 2
• Mixed cryoglobulinemia predicts worse outcomes even after SVR. 2

Common Pitfalls and How to Avoid Them

Pitfall 1: Using Sofosbuvir-Based Regimens in Severe Renal Impairment

How to avoid: Always calculate eGFR before prescribing; if <30 mL/min/1.73 m², use glecaprevir/pibrentasvir or elbasvir/grazoprevir instead. 2

Pitfall 2: Inadequate Drug-Drug Interaction Screening

How to avoid: Use specialized interaction checkers (AASLD/IDSA guidance or University of Liverpool) for all medications including over-the-counter and herbal supplements before prescribing DAAs. 1, 2

Pitfall 3: Treating Decompensated Cirrhosis with Glecaprevir/Pibrentasvir

How to avoid: Always assess Child-Pugh score; if Child-Pugh B or C, use sofosbuvir-based regimens with ribavirin, never glecaprevir/pibrentasvir. 2, 4

Pitfall 4: Deferring Treatment in Patients with F0–F2 Fibrosis

How to avoid: Recognize that all patients with chronic HCV should be scheduled for treatment; deferral increases risk of progression and transmission. 2

Pitfall 5: Inadequate Fibrosis Assessment

How to avoid: Always calculate FIB-4 score at minimum; if >3.25 or if clinical uncertainty exists, obtain additional non-invasive testing (transient elastography or proprietary serum markers) to accurately stage fibrosis and guide treatment duration. 1, 5, 6, 7